Abstract

Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder lacking effective targeted therapies. Mitochondrial dysfunction, marked by ATP depletion and excessive ROS production, lies at the heart of disease initiation and progression. This study presents a hierarchically targeted nanotherapeutic, Cu-CDs/Kyna@RM (RMCK), in which copper-doped, mitochondria-targeting carbon dots (Cu-CDs) are grafted with kynurenic acid (Kyna) and encapsulated within red blood cell-macrophage hybrid membranes. Upon systemic administration, RMCK homes to inflamed pancreatic tissue, where it sequentially releases Cu-CDs to target mitochondria, scavenge ROS, liberate Kyna, and restore mitochondrial function. It markedly improves survival, lowers serum amylase/lipase, attenuates pancreatic edema and necrosis, and prevents secondary lung injury, outperforming free Kyna therapy. In vitro, RMCK significantly reduces sodium taurocholate (STC)-induced acinar cell injury, measured by decreased cell necrosis and LDH release. Mechanistic studies including transcriptomics, immunohistochemistry, and functional assays reveal that RMCK amplifies GPR35-NF-κB inhibition to curb cytokine storms, prevents mtDNA-driven inflammasome activation, and alleviates hypoxia to downregulate HIF-1α and upregulate PPARγ for restored fatty acid oxidation. By integrating organ- and organelle-level targeting with ROS scavenging and mitochondrial energy remodeling, RMCK delivers synergistic, precision therapy for AP and offers a versatile platform for other inflammatory diseases characterized by mitochondrial dysfunction.